The present invention is directed to an improved process for forming isoxazolines and isoxazoles from nitroparaffins. The resultant products are useful in the formation of 1,3 amino alcohols and 1,3 ketoalcohols from the isoxazolines and 1,3-diketones and 1,3 ketoamines from the isoxazoles which are required in providing pharmaceutical agents. The resultant products are also known to be useful water treatment agents.
The reaction of nitroalkanes with phenyl isocyanate in the presence of a catalytic amount of triethylamine and with acetic anhydride in the presence of a base have been extensively studied. In the reaction of a primary nitroalkane with phenyl isocyanate as the dehydrating agent, one produces a nitrile oxide which dimerizes to produce a furoxan when run neat or, when in the presence of an olefin, an isoxazoline [T. Mukaiyama et al. J.A.C.S. 82, 5339 (1960); R. Husiegen Angew. Chem. 75 604 (1963)]. The utilization of an isocyanate presented several problems which included the cost and toxicity of the isocyanate as well as the ready deactivation of the isocyanate as a dehydrating agent by other materials in the reaction zone.
In the reaction of the primary nitroalkane with acetic anhydride, initial studies reported evidence which refuted a mechanism encompassing the formation of nitrile oxide intermediate. However, A. Rahman et al. Pak. J. Sci. Res. 30, 91-4 (1978) showed that when the reaction is conducted in the presence of a non-polar solvent and a dipolarophile, one does obtain isoxazoline. Acetic anhydride has been the reagent of choice by those skilled in this area because it is a readily available, inexpensive and is a liquid under ambient reaction conditions. Acetic anhydride can thus be easily dispensed into the reaction medium and has good solubility in common solvents. A final reason for viewing acetic anhydride as the desired dehydrating agent is its simple structure which is viewed as a means of inhibiting side reactions and possibly by-product formation. More recently, Rahman et al., in J. Chem. Soc. Pak. 5, 243-246 (1983) again showed that the nitrile oxide intermediate is formed by carrying the reaction out in the presence of an acetylenic compound as the dipolarophile to produce an isoxazole. Commercial utilization of this route has not been deemed suitable due to problems which include that the yield of the desired product is low, the acetic anhydride is consumed in the reaction, the conventional anhydride deemed useful yields by-products which are difficult to separate from the product mixture and the anhydride is an expensive material especially in view of the fact that it is consumed on a mole to mole basis with respect to the nitroalkane used.
It is desired to provide a process which can readily produce isoxazolines and isoxazoles in a manner which overcomes the defects discussed above. In particular, it is desired to provide a process which can form the desired product in high yields, which reduces by-product formation and provides an effective and efficient dehydrating agent.